Melanoma is a highly immunogenic tumor (Alexandrescu et al., “Immunotherapy for Melanoma: Current Status and Perspectives,” J. Immunother. 33(6):570-90 (2010)), yet tumor progression nevertheless occurs in immunocompetent patients. Escape of tumor from immune-mediated destruction can result from tumor release of soluble factors that redirect the immune response, or through mechanisms that limit or inhibit infiltration or function of tumor-infiltrating lymphocytes (“TILs”) (Loose & Van de Wiele, “The Immune System and Cancer,” Cancer Biother. Radiopharm. 24(3):369-76 (2009); Frey & Monu, “Signaling Defects in Anti-Tumor T Cells,” Immunol. Rev. 222:192-205 (2008); Alexandrescu et al., “Immunotherapy for Melanoma: Current Status and Perspectives,” J. Immunother. 33(6):570-90 (2010)). Therefore, a number of treatment strategies aim to augment anti-tumor immunity by targeting immunosuppressive mechanisms, including cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death receptor (PD1), thereby unrestraining existing tumor infiltrating lymphocytes (TIL) (Alexandrescu et al., “Immunotherapy for Melanoma: Current Status and Perspectives,” J. Immunother. 33(6):570-90 (2010)).
Despite the promise of these strategies in combination with existing therapies, and while select subsets of patients do respond strongly to immune-based therapies, because of the morbidity often associated with immunotherapeutics, clinicopathological criteria are sought to better identify those patients who will benefit from specific treatments and to select the optimal immunotherapeutic strategy.
Insights into identifying potential immunotherapeutic responders and novel immune targets in melanoma may be gained from treatment strategies in chronic inflammatory conditions, given the link between cancer and inflammation (Coussens & Werb, “Inflammation and Cancer,” Nature 420:860-7 (2002)). Anti-inflammatory agents suppress Th1 immunity which is needed for an effective anti-tumor response. Studies in multiple sclerosis and rheumatoid arthritis have shown that the sea anemone peptide ShK diminishes Th1 immunity by selectively blocking the voltage-gated potassium channel Kv1.3 on effector memory T-cells (Tem) (Beeton et al., “Kv1.3 Channels Are a Therapeutic Target for T Cell-Mediated Autoimmune Diseases,” Proc. Nat'l. Acad. Sci. U.S.A. 103:17414-9 (2006); Rangaraju et al., “Kv1.3 Potassium Channels as a Therapeutic Target in Multiple Sclerosis,” Expert Opin. Ther. Targets 13:909-24 (2009)). Kv1.3 blocking prevents the efflux of intracellular potassium, thereby diminishing the driving force for sustained calcium influx that is required for robust T-cell proliferation, cytokine production, and motility (Feske, “Calcium Signalling in Lymphocyte Activation and Disease,” Nat. Rev. Immunol. 7:690-702 (2007); Matheu et al., “Imaging of Effector Memory T Cells During a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block,” Immunity 29(4):602-14 (2008); Cahalan & Chandy, “The Functional Network of Ion Channels in T Lymphocytes,” Immunol. Rev. 231(1):59-87 (2009)). Matrix metalloproteinase (“MMP”)-23, a unique member of the MMP family characterized by its cysteine-rich toxin and immunoglobulin-like domains, contains a toxin domain, MMP-23(TxD), that is structurally similar to ShK, which also selectively blocks Kv1.3 channels (Rangaraju et al., “Potassium Channel Modulation by a Toxin Domain in Matrix Metalloprotease 23,” J. Biol. Chem. 285:9124-36 (2010)). The focus on tumor-derived MMPs in melanoma and other cancers, including breast, prostate, lung, and colon cancer, has been their ability to mediate microenvironmental changes regulating cancer progression, including the break down of extracellular matrix and promotion of growth/neoangiogenesis (Hofmann et al., “Matrix Metalloproteinases in Human Melanoma,” J. Invest. Dermatol. 115:337-44 (2000); Egeblad & Werb, “New Functions for the Matrix Metalloproteinases in Cancer Progression,” Nat. Rev. Cancer 2:161-74 (2002); Roy et al., “Matrix Metalloproteinases as Novel Biomarkers and Potential Therapeutic Targets in Human Cancer,” J. Clin. Oncol. 27:5287-97 (2009)). Further, a recent study by Bhardwaj and colleagues demonstrated a role for MMPs in influencing T-cell phenotype by showing that active MMP-2 induces Th2 skewing by blocking IL-12 and inducing OX40L on DCs (Godefroy et al., “Matrix Metalloproteinase-2 Conditions Human Dendritic Cells to Prime Inflammatory T(H)2 Cells Via an IL-12- and OX40L-Dependent Pathway,” Cancer Cell 19(3):333-46 (2011)). However, in general, the role of tumor-derived MMPs in the induction of immune escape has been less explored.
The present invention is directed to overcoming these and other deficiencies in the art.